SIV infection of macaques is an ideal model system in which to evaluate therapeutic compounds such as the immunophilin ligands because it recapitulates key features of HIV infection of the human CNS. We have developed an accelerated, consistent SIV/macaque model (SIV-AC) of HIV CNS disease in which over 90% of infected animals develop encephalitis with characteristic histopathological changes, psychomotor impairment and neurodegeneration. In this application we propose to use the SIV-AC model to examine the neuroprotective effects of the immunophilin ligand GPI-1485. Our hypothesis is that the severity of neurodegeneration in SIV-infected macaques is associated with production of specific neurotoxic products by cells of monocyte/macrophage origin in the brain, which in tum correlates with the level of virus replication in the CNS. We further hypothesize that the immunophilin ligand GPI-1485 will play a neuroprotective role in SIV-infected macaques by suppressing neurodegeneration despite the presence of infiltrating macrophages and active virus replication. These studies will help us further understand the central and peripheral nervous system manifestations of HIV infection and will provide a link between in vitro studies on the mechanisms by which immunophilin ligands suppress neurodegeneration (Projects 1 to 3) and clinical trials of GPI-1485 in humans (Project 5). The first Aim is to determine whether the severity of neurodegeration in SIV-infected macaques is associated with the levels of expression of specific macrophage-produced neurotoxins and/or with brain viral load. Aim 2 will determine whether administration of the immunophilin ligand GPI-1485 prevents or suppresses neurodegeration in the CNS of SIV-infected macaques. Aim 3 will determine whether administration of the immunophilin ligand GPI-1485 prevents or suppresses neurodegeration in the PNS of SIV-infected macaques. The final Aim will determine whether administration of the immunophilin ligand GPI-1485 slows the rate of nerve regeneration using a peripheral axotomy model.